Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Abstract Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient i...

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Bibliographic Details
Published in:Clinical immunology (Orlando, Fla.) Fla.), 2011-03, Vol.138 (3), p.321-330
Main Authors: Doetschman, Thomas, Sholl, Allyson, Chen, Hwu dau rw, Gard, Connie, Hildeman, David A, Bommireddy, Ramireddy
Format: Article
Language:English
Subjects:
Allergy and Immunology
Animals
Biological and medical sciences
Calcineurin
Calcineurin - genetics
Calcineurin - immunology
Cyclosporin A
Cytokines - biosynthesis
Cytokines - immunology
Forkhead Transcription Factors - immunology
FOXP3
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Hepatomegaly - immunology
Hepatomegaly - metabolism
Homeostasis - immunology
Inflammation
Knockout
Lymphocyte Activation - immunology
Mice
Mice, Mutant Strains
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Proto-Oncogene Proteins c-bcl-2 - immunology
Signal Transduction - immunology
Splenomegaly - immunology
Splenomegaly - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Transforming Growth Factor beta - immunology
Treg cells
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Summary:Abstract Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient in the CN catalytic subunit Aβ (CNAβ). Cnab−/− mice exhibit defective thymocyte maturation, splenomegaly and hepatomegaly. Further, as Cnab−/− mice age, they exhibit spontaneous T-cell activation and enhanced production of proinflammatory cytokines (IL-4, IL-6, and IFNγ). FOXP3+ Treg cells were significantly decreased in Cnab−/− mice likely contributing to increased T-cell activation. Interestingly, we found that CNAβ is critical for promotion of BCL-2 expression in FOXP3+ Treg and for permitting TGFβ signaling, as TGFβ induces FOXP3 in control but not in Cnab−/− T-cells. Together, these data suggest that CNAβ is important for the production and maintenance of Treg cells and to ensure mature T-cell quiescence.
ISSN:1521-6616
1521-7035
DOI:10.1016/j.clim.2010.12.020